Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross‐seeding behavior

Ghag, Gaurav; Bhatt, Nemil; Cantu, Daniel V.; Guerrero-Muñoz, Marcos J.; Ellsworth, Anna; Sengupta, Urmi; Kayed, Rakez

doi:10.1002/pro.3499

Cited by 95 publications

(81 citation statements)

References 55 publications

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“…In accordance with the observation that tau causes neuron death, mouse models that express tau mutations that cause frontotemporal dementias with tau pathology demonstrate neuron loss [68][69][70][71], early synapse loss, and disruption of neuronal network function [72][73][74][75][76][77]. As has been observed with Aβ, the forms of tau that may be toxic are the soluble, nonfibrillar, and highly reactive forms, the oligomers [78][79][80].…”

Section: Mechanisms Of Synapse Damage and Loss In Admentioning

confidence: 53%

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

et al. 2020

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Background: Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. The key points of this review include the following: Synapse loss is a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in AD. Synapse loss correlates most strongly with cognitive decline in AD because synaptic function underlies cognitive performance. Compounds that halt or reduce synapse damage or loss have a strong rationale as treatments of AD. Biomarkers that measure synapse degeneration or loss in patients will facilitate clinical development of such drugs. The ability of methods to sensitively measure synapse density in the brain of a living patient through synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, concentrations of synaptic proteins (e.g., neurogranin or synaptotagmin) in the cerebrospinal fluid (CSF), or functional imaging techniques such as quantitative electroencephalography (qEEG) provides a compelling case to use these types of measurements as biomarkers that quantify synapse damage or loss in clinical trials in AD. Conclusion: A number of emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD. These biomarkers hold promise both for use in diagnostics and in the measurement of therapeutic successes.

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Section: Mechanisms Of Synapse Damage and Loss In Admentioning

confidence: 53%

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

et al. 2020

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“…After shaking, the resulting TauO were purified by FPLC (Superdex 200 Increase 10/300 column, Amersham Biosciences). Aliquots of TauM were incubated with heparin (15 kDa) (1:5 molar ratio) to prepare TauF at 37 °C on an orbital shaker at a speed of 30 rpm for 5 days as described previously ( 89 ).…”

Section: Methodsmentioning

confidence: 99%

Modulating disease-relevant tau oligomeric strains by small molecules

Cascio

Garcia

Montalbano

et al. 2020

Journal of Biological Chemistry

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The pathological aggregation of tau plays an important role in Alzheimer’s disease (AD) and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies to disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including AD, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB), we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTOs-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.

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“…Tau oligomers often are considered the most toxic form of the protein (60,61). Mouse studies have shown that memory loss and synapse loss correlated better with oligomer concentration levels than with the amount or spreading of NFTs (62,63).…”

Section: Clr01 Reduces Tau Oligomers In the Hippocampus Dose-dependentlymentioning

confidence: 99%

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

Siddique

et al. 2020

Preprint

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Background: Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3×Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for one month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3×Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left the question whether CLR01 affected tau in vivo directly or indirectly open.Methods: To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3- or 1.0-mg/Kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.Results: CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.Conclusions: The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ) and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

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Soluble tau aggregates, not large fibrils, are the toxic species that display seeding and cross‐seeding behavior

Cited by 95 publications

References 55 publications

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

Modulating disease-relevant tau oligomeric strains by small molecules

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

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